The spectrum of propionic acidemia (PA) ranges from neonatal-onset to late-onset disease. Neonatal-onset PA, the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, coma, and death. It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. Late-onset PA includes developmental regression, chronic vomiting, protein intolerance, failure to thrive, hypotonia, and occasionally basal ganglia infarction (resulting in dystonia and choreoathetosis) and cardiomyopathy (Carrillo-Carrasco & Venditti, 2012 Gene Reviews). The incidence of PA has been estimated to be similar to that reported for methylmalonic acidemia, in the range of 1:35,000-1:70,000 (Saudubray et al., 1989 J Inherit Metab Dis. 12:25-41; Chace et al., 2001 Clinical Chemistry 47:2040-44). Propionic acidemia can be caused by mutations in one or both of genes encoding propionyl-CoA carboxylase (PCC); i.e., subunits PCCA or PCCB. PA can also result from a decrease in PCC activity from a lack of co-enzymes such as biotin. A collaborative report with the inventors found the incidence of PA carriers to be ˜5% in the Inuit population of Greenland, which is very high compared with those of most other autosomal recessive diseases (Ravn et al., 2000 Am J Hum Genet. 67:203-6). Biochemically, patients with this disorder present with elevated levels of propionyl CoA, propionic acid, methylcitrate, beta-hydroxy-propionate, propionylglycine, tiglic acid, and ketones. Ketones such as butanone may also be found in the urine (Menkes et al., 1966 The Journal of pediatrics. 69:413-21). Hyperammonemia originates secondarily from carbamoyl phosphate synthetase inhibition (Coude et al., 1979 Journal of Clinical Investigation. 64:1544-51; Stewart & Walser, 1980 Journal of Clinical Investigation. 66:484-92). Ketoacidotic episodes are frequently life threatening and ⅓ of affected neonates die within the first few weeks of life (Fenton et al., 2001 Disorders of propionate and methylmalonate metabolism in The Metabolic and Molecular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S. & Valle, D., eds) pp. 2165-2204, McGraw-Hill, Inc., New York). The condition can be treated by severely restricting protein intake; however, management of such patients is often difficult (Wolf et al., 1981 Journal of Pediatrics. 99:835-46). The inventors have previously demonstrated that human PCC is an α6β6 heterododecamer (Chloupkova et al., 2000 Mol Genet Metab. 71:623-32). The 72 kDa α subunit and the 56 kDa β subunit (Gravel et al., 1980 Archives of Biochemistry & Biophysics. 201:669-73; Kalousek et al., 1980 Journal of Biological Chemistry. 255:60-5) are encoded by separate genes designated, PCCA, found on chromosome 13 (Lamhonwah et al., 1986 Proc. Nat. Acad. Sci. 83:4864-8), and PCCB, found on chromosome 3 (Kraus et al., 1986 Proc. Nat. Acad. Sci. 83:2047-51), respectively. Both corresponding cDNAs have been sequenced (Kraus et al., 1986 Proc. Nat. Acad. Sci. 83:8049-53; Lamhonwah et al., 1989 Nucleic Acids Research. 17:4396; Lamhonwah et al., 1994 Genomics. 19:500-; Ohura et al., 1993 J Inherit Metab Dis. 16:863-7). The subunits are synthesized as longer precursors, imported into the mitochondrion, cleaved and assembled (Kraus et al., 1986 Proc. Nat. Acad. Sci. 83:8049-53; Browner et al., 1989 Journal of Biological Chemistry. 264:12680-5). The alpha subunit contains the sequence that accepts biotin (Kalousek et al., 1980 Journal of Biological Chemistry. 255:60-5; Lamhonwah et al., 1987 Archives of Biochemistry & Biophysics. 254:631-6; Leon-Del-Rio & Gravel 1994 Journal of Biological Chemistry. 269:22964-8); it also binds CO2, Mg2+, ATP, and can be up regulated by binding K+ (Kalousek et al., 1980 Journal of Biological Chemistry. 255:60-5). The beta □subunit binds propionyl-CoA (Fenton et al., 2001 Disorders of propionate and methylmalonate metabolism in The Metabolic and Molecular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S. & Valle, D., eds) pp. 2165-2204, McGraw-Hill, Inc., New York). Mutations in either gene result in PA. To date, 81 and 86 mutations have been identified in the PCCA and PCCB genes from propionic acidemia patients, respectively (a public continuously updated list of all reported PCC mutations can be found at the Kraus lab webpage at the University of Colorado-Denver Medical School).
Currently, there is no cure for PA or other PCC-deficiency related conditions and current treatment provides only partial alleviation of symptoms. Enzyme therapy is a therapeutic approach in which the deficient enzyme is replaced by recombinant active protein. The inventors aim to develop a way to deliver active PCC to afflicted patients. However, the ability to specifically deliver PCC to the mitochondria presents a challenge. Thus there remains a need in this art to develop compositions, including pharmaceutical compositions, and methods for delivering active PCC to the intracellular mitochondrial site of its activity to ameliorate deficits and deficiencies thereof.